Trifluoromethyl-substituted alcohols of formula (I) have been described as ligands that bind to the glucocorticoid receptor. These compounds are potential therapeutics in treating a number of diseases modulated by glucocorticoid receptor function, including inflammatory, autoimmune and allergic disorders. Examples of these compounds are described in U.S. Patent Application Publication Nos. 2003/0232823, 2004/0029932, and 2004/0023999, which are each incorporated herein by reference in their entireties and are hereinafter termed “the Trifluoromethyl-Substituted Alcohol Patent Applications”.

It is well known in the art that enantiomers of a particular compound can have different biological properties including efficacy, toxicity, and pharmacokinetic properties. Thus, it is often desirable to administer one enantiomer of a racemic therapeutic compound.
The synthetic methods disclosed in the patent applications cited above describe the synthesis of racemic products. Separation of enantiomers was accomplished by chiral HPLC and may be accomplished by other conventional ways of separating enantiomers. Chiral HPLC and other enantiomer separation method, however, are generally unsuitable for large-scale preparation of a single enantiomer. Thus, a stereoselective synthesis for preparation of these compounds would be highly desirable.
The present invention discloses a stereoselective synthesis of certain compounds of Formula (X) or (X′)
which are key intermediates in the synthesis of enantiomerically pure compounds of Formula (I).
The key step involves a diastereoselective addition of chiral sulfoxide anion to a trifluoromethyl ketone to form a chiral β-hydroxy-β-trifluoromethyl-sulfoxide adduct. In the literature there are limited examples of such diastereoselective addition to fluorinated ketones, e.g., P. Bravo et al., J. Chem. Soc., Perkin Trans. I 1995, 1667; P. Bravo et al., J. Org. Chem. 1990, 55, 4216; C. Mioskowski and G. Solladie, Tetrahedron 1980, 36, 227. In these examples, the authors did not convert these adducts to the corresponding chiral epoxides. A. Arnone et al., Tetrahedron Lett. 1996, 37, 3903, describe an enzymatic reduction method for the synthesis of chiral β-hydroxy-β-trifluoromethyl thiol ether and its subsequent conversion to a chiral trifluoromethyl-substituted epoxide.